Symptomatic knee osteoarthritis affects 6% of the U.S. adult population and 12-13% of those age 60 and over (Felson and Zhang, 1998). Medical treatment often fails to provide full relief of pain and disability, and there are no known treatments to prevent disease progression. A multicenter 5 year observational study of those with knee OA and those at high risk of disease with repeated knee MRIs on all subjects, the Osteoarthritis Initiative (OAI) represents the best opportunity ever to identify risk factors for OA. Despite its richness of measurements, there is one recently identified risk factor for progression, malalignment on full limb x-rays that is not being comprehensively assessed in OAI. Full limb films to assess alignment are being acquired in those with frequent knee pain and x-ray OA at baseline but not in other subjects and there is no plan for their reading. While published data suggest that malalignment is the most potent yet identified risk factor for structural progression in those with knee OA, there are no data on whether alignment of the limb affects the risk of developing new symptomatic knee OA or new structural disease. Further, there are preliminary data that the limb's alignment status affects whether other known risk factors for OA such as obesity and muscle weakness affect the risk of progression, or whether it affects. There are two critical unstudied issues regarding alignment that are addressed by this project: 1) whether alignment affects disease in those without symptomatic OA at baseline and 2) whether the malalignment status of a limb determines the effect on disease of other known and putative risk factors for knee OA. We hypothesize that all modifiable risk factors that act through joint loading will have different effects on the trajectory of knee OA if the limb is malaligned than if the limb is neutrally aligned. In limbs with severe malalignment, progression of disease will be inevitable, and risk factors will have little effect on worsening. In graphing the risk of disease worsening associated with a modifiable risk factor (e.g. obesity) by alignment, we postulate an inverted U shaped curve -- low risks for obesity when limbs are neutrally aligned and when limbs are severely malaligned, high risks associated with obesity when limbs are moderately malaligned. This hypothesis has profound implications on opportunities for OA prevention and on the development of treatments for OA. The aims of this grant are: 1. To evaluate whether the limb's mechanical axis on full limb films increases the risk of cartilage loss and worsening knee pain in those with and without OA at baseline;2. To test whether there is a threshold of severe malalignment above which cartilage loss and knee pain development or progression are universal;3. To evaluate whether known and putative risk factors for OA affect OA differently when limbs are malaligned than when limbs are neutrally aligned, a. To test whether the effect of obesity differs by alignment;b. To examine whether effects of muscle strength on knee OA differ by alignment status. c. To evaluate whether habitual physical activity affects OA differently in limbs with neutral alignment than in those with malalignment;4. To develop proxy measures for alignment that can be used in other studies. In addition to addressing these questions, this project will complete the reading of alignment films and make these data available in the OAI data set and will provide also critical readings of cartilage volume loss on MRI in OAI subjects, data that would otherwise not be supported.